Antisense oligonucleotide-mediated knockdown therapy in two infants with severe KCNT1 epileptic encephalopathy

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• KCNT1-related epileptic encephalopathy, including epilepsy of infancy with migrating focal seizures, is a severe neurodevelopmental disorder.
• It is caused by de novo genetic variants in KCNT1, leading to overactive Slack potassium channels, cortical hyperexcitability, and refractory seizures.
• Pathogenic KCNT1 variants can increase neuronal potassium currents by up to 40%.

Purpose of the Study:

• To investigate antisense oligonucleotide-mediated KCNT1 knockdown as a therapeutic strategy for epilepsy of infancy with migrating focal seizures.
• To assess the efficacy and safety of intrathecal KCNT1-targeting antisense oligonucleotides in patients with KCNT1 mutations.

Main Methods:

• Intrathecal delivery of an experimental, non-allele-specific, KCNT1-targeting antisense oligonucleotide via lumbar puncture.
• Treatment administered to two 2-year-old females with the severe, recurrent KCNT1 p.R474H pathogenic variant.

Main Results:

• A significant reduction in seizure frequency and intensity was observed in both patients.
• Both patients developed ventricular enlargement or hydrocephalus following treatment.
• In one patient, the toxicity prompted a redirection of the goals of care.

Conclusions:

• Intrathecal KCNT1 knockdown using antisense oligonucleotides may be a potential therapeutic strategy for KCNT1-related epileptic encephalopathy.
• Ventricular enlargement/hydrocephalus represents a potential monitorable toxicity of intrathecal antisense oligonucleotides.
• Further research is needed to optimize delivery and mitigate potential adverse effects.